Tricyclic Angiotensin II Agonists

ABSTRACT

There is provided compounds of formula I, 
     
       
         
         
             
             
         
       
     
     wherein the dotted line, X 1 , X 2 , X 3 , A, Y 1 , Y 2 , Y 3 , Y 4 , Z 1 , Z 2 , R 2  and R 3  have meanings given in the description, and pharmaceutically-acceptable salts thereof, which compounds are useful as selective agonists of the AT2 receptor, and thus, in particular, in the treatment of inter alia gastrointestinal conditions, such as dyspepsia, IBS and MOF, and cardiovascular disorders.

FIELD OF THE INVENTION

This invention relates to novel pharmaceutically-useful compounds, inparticular compounds that are angiotensin II (AngII) agonists, moreparticularly agonists of the AngII type 2 receptor (hereinafter the AT2receptor), and especially agonists that bind selectively to thatreceptor. The invention further relates to the use of such compounds asmedicaments, to pharmaceutical compositions containing them, and tosynthetic routes to their production.

BACKGROUND AND PRIOR ART

The endogenous hormone AngII is a linear octapeptide(Asp¹-Arg²-Val³-Tyr⁴-Ile⁵-His⁶-Pro⁷-Phe⁸), and is the active componentof the renin-angiotensin system (RAS). It is produced by the sequentialprocessing of the pro-hormone angiotensinogen by renin and angiotensinconverting enzyme (ACE).

The renin-angiotensin system (RAS) plays an important role in theregulation of blood pressure, body fluid and electrolyte homeostasis.Ang II exerts these physiological actions in many organs including thekidneys, the adrenal glands, the heart, blood vessels, the brain, thegastrointestinal tract and the reproductive organs (de Gasparo et al,Pharmacol. Rev. (2000) 52, 415-472).

Two main classes of AngII receptors have been identified, and designatedas the type 1 receptor (hereinafter the AT1 receptor) and the AT2receptor. The AT1 receptor is expressed in most organs, and is believedto be responsible for the majority of the biological effects of AngII.The AT2 receptor is more prevalent than the AT1 receptor in fetaltissues, the adult ovaries, the adrenal medulla and the pancreas. Anequal distribution is reported in the brain and uterus (Ardaillou, J.Am. Soc. Nephrol., 10, S30-39 (1999)).

Several studies in adult individuals appear to demonstrate that, in themodulation of the response following AngII stimulation, activation ofthe AT2 receptor has opposing effects to those mediated by the AT1receptor.

The AT2 receptor has also been shown to be involved in apoptosis andinhibition of cell proliferation (see de Gasparo et al, supra). Further,it seems to play a role in blood pressure control. For example, it hasbeen shown in transgenic mice lacking AT2 receptors that their bloodpressure was elevated. Furthermore, it has been concluded that the AT2receptor is involved in exploratory behaviour, pain sensitivity andthermoregulation.

The expression of AT2 receptors has also been shown to increase duringpathological circumstances, such as vascular injury, wound healing andheart failure (see de Gasparo et al, supra).

The expected pharmacological effects of agonism of the AT2 receptor aredescribed generally in de Gasparo et al, supra.

More recently, AT2 receptor agonists have been shown to be of potentialutility in the treatment and/or prophylaxis of disorders of thealimentary tract, such as dyspepsia and irritable bowel syndrome, aswell as multiple organ failure (see international patent application WO99/43339).

AngII antagonists (which bind to the AT1 and/or AT2 receptors) have beendisclosed in inter alia international applications WO 93/04045, WO93/04046, WO 94/11379 and WO 94/28896, U.S. Pat. Nos. 5,312,820 and5,512,681, European patent applications EP 0 499 415, EP 399 731 and EP399 732, Pandya et al, Bioorganic & Medicinal Chemistry, 9, 291-300(2001) and Chang et al, Bioorganic & Medicinal Chemistry Letters, 4,2787-2792 (1994). The use of the compounds disclosed in these documentsas agonists of AngII, and in particular the AT2 receptor, is notcontemplated.

U.S. Pat. No. 5,444,067 discloses compounds comprising an imidazolylgroup attached, via a methylene bridge, to a phenylthiophene moiety, asAngII agonists. The phenyl ring of the phenylthiophene moiety in thesemolecules is 1,4-disubstituted with the thiophene and the imidazolylgroup (which is attached via a methylene bridge).

More recently, international patent applications WO 02/96883, WO03/064414, WO 2004/085420, WO 2004/046128, WO 2004/046141 and WO2004/046137 have disclosed various multicyclic compounds as agonists ofAngII and in particular as selective AT2 receptor agonists. In thecompounds disclosed in these documents, a central aryl ring isdisubstituted in the 1,4 (para) configuration. None of these documentsmention or suggest compounds in which such an aryl group isdisubstituted in the 1,3 (meta) configuration.

We have now found that such compounds are effective and/or selective AT2receptor agonists and are therefore expected to find utility in interalia the above-mentioned conditions.

DISCLOSURE OF THE INVENTION

According to the invention there is provided a compound of formula I,

whereinX₁ represents —C(R^(1a))(R^(1b))—, —N(R^(1a))— or —O—;the dotted line signifies an optional double bond; andin the case when the dotted line does not signify a double bond, X₂ andX₃ independently represent —C(R^(1c))(R^(1d))—, —N(R^(1e))—, —O—, —C(O)—or —C(R^(1f))(R^(1g))—C(R^(1h))(R^(1j))— provided that:

-   (i) when X₁ represents —N(R^(1a))—, then X₂ and X₃ do not both    represent N(R^(1e))—;-   (ii) when X₁ represents —O—, then X₂ and X₃ do not both represent    —O—;-   (iii) when X₁ represents —O— and X₂ represents —N(R^(1e)—, then X₃    represents —C(O)—; and-   (iv) when X₁ represents —O— and X₃ represents —N(R^(1e))—, then X₂    does not represent —C(R^(1c))(R^(1d))—; or    in the case when the dotted lines signifies a double bond, X² and X³    independently represent —N— or —C(R^(1c))—;    R^(1a), R^(1b), R^(1c), R^(1e), R^(1f), R^(1g), R^(1h) and R^(1j)    independently represent H, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxy-C₁₋₆    alkyl, Ar¹, Het¹, C₁₋₃ alkyl-Ar², C₁₋₃ alkyl-Het², C₁₋₃ alkoxy-Ar³,    C₁₋₃ alkoxy-Het³, halo, —C(O)—C₁₋₆ alkyl, —C(O)—Ar⁴ or —C(O)—Het⁴;    Ar¹, Ar², Ar³ and Ar⁴ each independently represent a C₆₋₁₀ aryl    group, which group is optionally substituted by one or more    substituents selected from ═O, —OH, cyano, halo, nitro, C₁₋₆ alkyl    (optionally terminated by —N(H)C(O)OR^(11a)), C₁₋₆ alkoxy, phenyl,    —N(R^(12a))R^(12b), —C(O)R^(12c), —C(O)OR^(12d),    —C(O)N(R^(12e))R^(12f), —N(R^(12g))C(O)R^(12h),    —N(R^(12i))C(O)N(R^(12j))R^(12k), —N(R^(12m))S(O)₂R^(11b),    —S(O)_(p)R^(11c), —OS(O)₂R^(11d) and —S(O)₂N(R^(12n))R^(12p);    Het¹, Het², Het³ and Het⁴ each independently represent a four- to    twelve-membered heterocyclic group containing one or more    heteroatoms selected from oxygen, nitrogen and/or sulfur, which    heterocyclic group is optionally substituted by one or more    substituents selected from ═O, —OH, cyano, halo, nitro, C₁₋₆ alkyl    (optionally terminated by —N(H)C(O)OR^(11a)), C₁₋₆ alkoxy, phenyl,    —N(R^(12a))R^(12b), —C(O)R^(12c), —C(O)OR^(12d),    —C(O)N(R^(12e))R^(12f), —N(R^(12g))C(O)R^(12h),    —N(R^(12i))C(O)N(R^(12j))R^(12k), —N(R^(12m))S(O)₂R^(11b),    —S(O)_(p)R^(11c), —OS(O)₂R^(11d) and —S(O)₂N(R^(12n))R^(12p);    R^(11a) to R^(11d) independently represent, on each occasion when    used herein, C₁₋₆ alkyl;    R^(12a) to R^(12p) independently represent, on each occasion when    used herein, H or C₁₋₆ alkyl;    p represents 0, 1 or 2;    A represents —C(O) or —CH₂—;    Y₁, Y₂, Y₃ and Y₄ independently represent —CH— or —CF—;    Z₁ represents —CH—, —O—, —S—, —N— or —CH═CH—;    Z₂ represents —CH—, —O—, —S— or —N—;    provided that:-   (a) Z₁ and Z₂ are not the same;-   (b) when Z₁ represents —CH═CH—, then Z₂ may only represent —CH— or    —N—; and-   (c) other than in the specific case in which Z₁ represents —CH═CH—,    and Z₂ represents —CH—, when one Z₁ and Z₂ represents —CH—, then the    other represents —O— or —S—;    R² represents —S(O)₂N(H)C(O)R⁴, —S(O)₂N(H)S(O)₂R⁴, —C(O)N(H)S(O)₂R⁴,    or, when Z₁ represents —CH═CH—, R² may represent    —N(H)S(O)₂N(H)C(O)R⁵ or —N(H)C(O)N(H)S(O)₂R⁵;    R³ represents C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxy-C₁₋₆-alkyl or    di-C₁₋₃-alkylamino-C₁₋₄-alkyl;    R⁴ represents C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxy-C₁₋₆-alkyl, C₁₋₃    alkoxy-C₁₋₆-alkoxy, C₁₋₆ alkylamino or di-C₁₋₆ alkylamino; and    R⁵ represents C₁₋₆ alkyl,    or a pharmaceutically-acceptable salt thereof,    which compounds and salts are referred to together hereinafter as    “the compounds of the invention”.

Pharmaceutically-acceptable salts include acid addition salts and baseaddition salts. Such salts may be formed by conventional means, forexample by reaction of a free acid or a free base form of a compound ofthe invention with one or more equivalents of an appropriate acid orbase, optionally in a solvent, or in a medium in which the salt isinsoluble, followed by removal of said solvent, or said medium, usingstandard techniques (e.g. in vacuo or by freeze-drying). Salts may alsobe prepared by exchanging a counter-ion of a compound of the inventionin the form of a salt with another counter-ion, for example using asuitable ion exchange resin.

Unless otherwise specified, alkyl groups, and the alkyl parts of alkoxy,alkoxyalkyl, alkoxyalkoxy, alkylamino, alkylaminoalkyl, alkyl-aryl,alkyl-heterocyclic groups, alkoxy-aryl and alkoxy-heterocyclic groups,as defined herein may be straight-chain or, when there is a sufficientnumber (i.e. a minimum of two or three, as appropriate) of carbon atoms,be branched-chain, and/or cyclic. Further, when there is a sufficientnumber (i.e. a minimum of four) of carbon atoms, such groups may also bepart cyclic/acyclic. Such alkyl groups, and alkyl parts of alkoxy,alkoxyalkyl, alkoxyalkoxy, alkylamino, alkylaminoalkyl, alkyl-aryl,alkyl-heterocyclic, alkoxy-aryl and alkoxy-heterocyclic groups may alsobe saturated or, when there is a sufficient number (i.e. a minimum oftwo) of carbon atoms, be unsaturated. Unless otherwise specified, suchgroups may also be substituted by one or more halo, and especiallyfluoro, atoms.

For the avoidance of doubt, alkoxy and alkoxyalkoxy groups are attachedto the rest of the molecule via the/an oxygen atom in that group,alkylamino groups are attached to the rest of the molecule via thenitrogen atom of the amino part of that group, alkoxyalkyl,alkylaminoalkyl, alkyl-aryl and alkyl-heterocyclic groups are attachedto the rest of the molecule via the alkyl part of that group, andalkoxy-aryl and alkoxy-heterocyclic groups are attached to the rest ofthe molecule via the alkyl part of the alkoxy part of that group.

The term “halo”, when used herein, includes fluoro, chloro, bromo andiodo.

For the avoidance of doubt, in cases in which the identity of two ormore substituents in a compound of the invention (for example any two ormore of the substituents R^(1a) to R^(1j)) may be the same, the actualidentities of the respective substituents are not in any wayinterdependent. For example, in the situation in which two or more ofR^(1a) to R^(1j) represent C₁₋₆ alkyl groups, the alkyl groups inquestion may be the same or different. Similarly, when aryl andheterocyclic groups are substituted by more than one substituent asdefined herein, the identities of the individual substituents are not tobe regarded as being interdependent.

C₆₋₁₀ aryl groups include phenyl, naphthyl and the like (preferablyphenyl). Preferred optional substituents on aromatic groups includehalo, —OH, cyano, nitro, C₁₋₆ (e.g. C₁₋₃) alkoxy groups and, moreparticularly, C₁₋₆ (e.g. C₁₋₃) alkyl groups (such as methyl).

Het (Het¹, Het², Het³ and Het⁴) groups that may be mentioned includethose containing 1 to 4 heteroatoms (selected from the group oxygen,nitrogen and/or sulfur) and in which the total number of atoms in thering system are between five and twelve. Het (Het¹, Het², Het³ and Het⁴)groups may be fully saturated, wholly aromatic, partly aromatic and/orbicyclic in character. Heterocyclic groups that may be mentioned includebenzodioxanyl, benzodioxepanyl, benzodioxolyl, benzofuranyl,benzofurazanyl, benzimidazolyl, benzomorpholinyl, benzothiophenyl,chromanyl, cinnolinyl, dioxanyl, furanyl, hydantoinyl, imidazolyl,imidazo[1,2-a]pyridinyl, indolyl, isoquinolinyl, isoxazolyl, maleimido,morpholinyl, oxazolyl, phthalazinyl, piperazinyl, piperidinyl, purinyl,pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimindinyl, pyrrolidinonyl,pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl,3-sulfolenyl, tetrahydropyranyl, tetrahydrofuranyl, thiazolyl,thiophenyl, thiochromanyl, triazolyl, tetrazolyl and the like. Values ofHet¹ that may be mentioned include thiophenyl, furanyl, pyridinyl andthiazolyl. Values of Het² that may be mentioned include pyridinyl,furanyl, thiophenyl and thiazolyl. Values of Het³ and Het⁴ that may bementioned include pyridinyl.

Substituents on Het (Het¹, Het², Het³ and Het⁴) groups may, whereappropriate, be located on any atom in the ring system including aheteroatom. The point of attachment of Het (Het¹, Het², Het³ and Het⁴)groups may be via any atom in the ring system including (whereappropriate) a heteroatom, or an atom on any fused carbocyclic ring thatmay be present as part of the ring system. Het (Het¹, Het², Het³ andHet⁴) groups may also be in the N- or S-oxidised form.

Preferred ring systems comprising the substituents Y₁, Y₂, Y₃ and Y₄include phenyl groups. For the avoidance of doubt, the ring systems incompounds of formula I that comprise the groups Z₁ and Z₂, are aromaticin nature. In some instances, for example in cases where one of Z₁ andZ₂ represents —N—, the skilled person will appreciate that an additionalH atom may necessarily be bonded to that N atom, in order to ensure thatthe rules of valency are adhered to. Preferred ring systems comprisingZ₁ and Z₂ include oxazole groups, thiazole groups, pyridinyl groups,furanyl groups and, more particularly, thiophenyl groups and phenylgroups.

In this respect, compounds of the invention may exhibit tautomerism. Alltautomeric forms and mixtures thereof are included within the scope ofthe invention.

Compounds of the invention also contain one or more asymmetric carbonatoms and may therefore exhibit optical and/or diastereoisomerism.Diastereoisomers may be separated using conventional techniques, e.g.chromatography or fractional crystallisation. The various stereoisomersmay be isolated by separation of a racemic or other mixture of thecompounds using conventional, e.g. fractional crystallisation or HPLC,techniques. Alternatively the desired optical isomers may be made byreaction of the appropriate optically active starting materials underconditions which will not cause racemisation or epimerisation, or byderivatisation, for example with a homochiral acid followed byseparation of the diastereomeric derivatives by conventional means (e.g.HPLC, chromatography over silica). All stereoisomers are included withinthe scope of the invention.

Compounds of the invention that may be mentioned include those in which,when Z₁ represents —CH═CH—, Z₂ represents —CH—, R² represents—S(O)₂N(H)C(O)R⁴, R³ represents n-propyl, Y₁, Y₂ and Y₃ all represent—CH—, A represents —CH₂—, the dotted line signifies a double bond, X₁represents —N(R^(1a))—, X₂ represents —N—, X₃ represents —C(R^(1c))— andR^(1c) represents n-butyl, then:

-   (a) when Y₄ represents —CF— and R^(1a) represents a    2-chloro,5-acetamidophenyl group, then R⁴ does not represent    t-butoxy or ethoxy; and-   (b) when Y₄ represents —CH— and R^(1a) represents a    2-trifluoromethylphenyl group, then R⁴ does not represent t-butoxy.

Further compounds of the invention that may be mentioned include thosein which:

-   (i) R^(1c) represents C₁₋₃ alkyl, C₅₋₆ alkyl or, more preferably, H,    C₁₋₆ alkoxy, C₁₋₆ alkoxy-C₁₋₆ alkyl, Ar¹, Het¹, C₁₋₃ alkyl-Ar², C₁₋₃    alkyl-Het², C₁₋₃ alkoxy-Ar³, C₁₋₃ alkoxy-Het³, halo, —C(O)—C₁₋₆    alkyl, —C(O)—Ar⁴ or —C(O)-Het⁴;-   (ii) R^(1c) does not represent n-butyl; or-   (iii) R^(1c) represents H.

Preferred compounds of the invention include those in which:

the dotted line does not signify a double bond;X₁ represents —C(R^(1a))(R^(1b))— or —N(R^(1a))—;X₂ represents —O—, —N(R^(1e))— or, more preferably, —C(R^(1c))(R^(1d))—;X₃ represents —O—, —C(R^(1f))(R^(1g))—C(R^(1h))(R^(1j))— or, morepreferably, —C(R^(1c))(R^(1d))— or —C(O)—;R^(1a) represents H or C₁₋₃ alkyl, such as methyl;R^(1b) represents C₁₋₃ alkyl, such as methyl, or, especially, H;R^(1c) represents C₁₋₃ alkyl, such as methyl, or, especially, H;R^(1d) represents C₁₋₃ alkyl, such as methyl, or, especially, H.

More preferred compounds of the invention include those in which:

X₁ represents —CH₂— or —N(CH₃)—;X₂ represents —CH₂—;X₃ represents —CH₂— or —C(O)—;A represents —CH₂—;Y₁, Y₂, Y₃ and Y₄ all represent —CH—;Z₁ represents —CH═CH— or, especially, —S—;Z₂ represents —CH—;R² represents —S(O)₂N(H)C(O)R⁴;R³ represents C₁₋₄ alkyl such as n-butyl or, particularly, iso-butyl;R⁴ represents C₁₋₄ alkoxy-C₁₋₃ alkyl or C₁₋₄ alkoxy (such asn-butoxymethyl, iso-butoxy and, especially, n-butoxy).

When R² represents —S(O)₂N(H)C(O)R⁴, —S(O)₂N(H)S(O)₂R⁴ or—C(O)N(H)S(O)₂R⁴, preferred values of R⁴ include n-butoxymethyl,iso-butoxy and especially, n-butoxy.

Preferred ring systems comprising the groups X₁, X₂ and X₃ includeoptionally substituted 2-pyrrolidinon-1-yl groups,2,5-pyrrolidindion-1-yl and hydantoin-3-yl groups. Preferred optionalsubstituents include C₁₋₃ alkyl (e.g. methyl).

More preferred compounds of the invention include the compounds of theexamples described hereinafter.

Compounds of formula I may be made in accordance with techniques wellknown to those skilled in the art, for example as described hereinafter.

According to a further aspect of the invention there is provided aprocess for the preparation of a compound of formula I, which processcomprises:

(i) for compounds of formula I in which R² represents —S(O)₂N(H)C(O)R⁴or —S(O)₂N(H)S(O)₂R⁴, and R⁴ is as hereinbefore defined, reaction of acompound of formula II,

wherein the dotted line, X₁, X₂, X₃, A, Y₁, Y₂, Y₃, Y₄, Z₁, Z₂ and R³are as hereinbefore defined with a compound of formula III,

R⁴GL¹  III

wherein G represents —C(O)— or —S(O)₂— (as appropriate), L¹ represents asuitable leaving group, such as halo (e.g. chloro or bromo) and R⁴ is ashereinbefore defined, for example at around room temperature or above(e.g. up to 60-70° C.) in the presence of a suitable base (e.g.pyrrolidinopyridine, pyridine, triethylamine, tributylamine,trimethylamine, dimethylaminopyridine, di-iso-propylamine,1,8-diazabicyclo[5.4.0]undec-7-ene, sodium hydroxide, sodium carbonate,or mixtures thereof) and an appropriate solvent (e.g. pyridine,dichloromethane, chloroform, tetrahydrofuran, dimethylformamide,trifluoromethylbenzene, triethylamine, water, or mixtures thereof).Preferred base/solvent systems for compounds of formula III in which Gis —C(O)— include pyrrolidinopyridine/pyridine,pyrrolidinopyridine/triethylamine, dimethylaminopyridine/pyridine,dimethyl-aminopyridine/triethylamine, sodiumcarbonate/dichloromethane/water orpyrrolidinopyridine/triethylamine/dichloromethane. Preferredbase/solvent systems for compounds of formula III in which G is —S(O)₂—include NaOH/THF;(ii) for compounds of formula I in which R² represents —S(O)₂N(H)C(O)R⁴and R⁴ represents C₁₋₆ alkoxy-C₁₋₆-alkyl, coupling of a compound offormula II as hereinbefore defined with a compound of formula IV,

R^(4a)CO₂H  IV

wherein R^(4a) represents C₁₋₆ alkoxy-C₁₋₆-alkyl, for example undersimilar conditions to those described under process step (i) above, inthe presence of a suitable coupling reagent (e.g.1,1′-carbonyl-diimidazole, N,N′-dicyclohexylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,N,N′-disuccinimidyl carbonate,benzotriazole-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate,2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate, benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate, bromo-tris-pyrrolidinophosphoniumhexafluorophosphate or2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumtetrafluorocarbonate), a suitable base (as mentioned in process step (i)above) and an appropriate solvent (as mentioned in process step (i)above);(iii) for compounds of formula I in which R² represents —C(O)N(H)S(O)₂R⁴and R⁴ is as hereinbefore defined, coupling of a compound of formula V,

wherein the dotted line, X₁, X₂, X₃, A, Y₁, Y₂, Y₃, Y₄, Z₁, Z₂ and R³are as hereinbefore defined with a compound of formula VI,

R⁴S(O)₂NH₂  VI

wherein R⁴ is as hereinbefore defined, for example in the presence of asuitable coupling reagent (such as those described in process step (ii)hereinbefore), and under similar reaction conditions to those describedhereinbefore for preparation of compounds of formula I in which R²represents —S(O)₂N(H)C(O)R⁴ and R⁴ represents C₁₋₆ alkoxy-C₁₋₆-alkyl(i.e. process step (ii));(iv) for compounds of formula I in which R² represents —C(O)N(H)S(O)₂R⁴and R⁴ is as hereinbefore defined, coupling of a compound of formulaVII,

wherein the dotted line, X₁, X₂, X₃, A, Y₁, Y₂, Y₃, Y₄, Z₁, Z₂ and R³are as hereinbefore defined with a compound of formula VIII,

R⁴S(O)₂Cl  VIII

wherein R⁴ is as hereinbefore defined, for example at around 50° C. inthe presence of a suitable base (e.g. sodium hydride) and an appropriateorganic solvent (e.g. THF);(v) for compounds of formula I in which R² represents—N(H)S(O)₂N(H)C(O)R⁵ and R⁵ is as hereinbefore defined, reaction of acompound of formula IX,

wherein the dotted line, X₁, X₂, X₃, A, Y₁, Y₂, Y₃, Y₄, Z₁, Z₂ and R³are as hereinbefore defined with a compound of formula X,

R⁵C(O)N(H)S(O)₂Cl  X

wherein R⁵ is as hereinbefore defined, for example at or around roomtemperature in the presence of a suitable base (e.g. sodium hydroxide ortriethylamine) and a suitable organic solvent (e.g. benzene ordichloromethane);(vi) for compounds of formula I in which R² represents—N(H)C(O)N(H)S(O)₂R⁵ and R⁵ is as hereinbefore defined, reaction of acompound of formula IX as hereinbefore defined with a compound offormula XI,

R⁵S(O)₂N(H)C(O)R^(x)  XI

wherein R^(x) represents a suitable leaving group, such as a halo (e.g.chloro or bromo) group or alkoxy (e.g. —O—C₁₋₂ alkyl) and R⁵ is ashereinbefore defined, for example at or around room temperature in thepresence of a suitable organic solvent (e.g. dichloromethane).Alternatively R^(x) may represent —OH, in which case the couplingreaction may be performed under conditions such as those hereinbeforedescribed in respect of process (ii) above;(vii) for compounds of formula I in which R² represents—N(H)C(O)N(H)S(O)₂R⁵ and R⁵ is as hereinbefore defined, reaction of acompound of formula IX as hereinbefore defined with an isocyanatecompound of formula XII,

R⁵S(O)₂NCO  XII

wherein R⁵ is as hereinbefore defined, for example at or around roomtemperature in the presence of a suitable organic solvent (e.g.dichloromethane);(viii) for compounds of formula I in which R² represents—S(O)₂N(H)C(O)R⁴ and R⁴ represents C₁₋₆ alkylamino, reaction of acompound of formula II as hereinbefore defined with an isocyanatecompound of formula XIII,

R^(4b)NCO  XIII

wherein R^(4b) is C₁₋₆ alkyl, for example at or around room temperaturein the presence of a suitable base (e.g. sodium hydroxide or potassiumhydroxide and an appropriate organic solvent (e.g. acetone oracetonitrile); or(ix) for compounds of formula I in which R² represents —S(O)₂N(H)C(O)R⁴and R⁴ represents di-C₁₋₆ alkylamino, reaction of a correspondingcompound of formula I in which R² represents —S(O)₂N(H)C(O)R⁴ and R⁴represents C₁₋₆ alkoxy with a compound of formula XIV,

R^(4c)N(H)R^(4d)  XIV

wherein R^(4c) and R^(4d) independently represent C₁₋₆ alkyl, forexample at above room temperature (e.g. at between 70° C. and 100° C.)in the presence of an appropriate organic solvent (e.g. toluene).

Compounds of formula V may be prepared by oxidation of a compound offormula XV,

wherein the dotted line, X₁, X₂, X₃, A, Y₁, Y₂, Y₃, Y₄, Z₁, Z₂ and R³are as hereinbefore defined, for example under standard oxidationconditions in the presence of a suitable oxidising agent, such aspotassium permanganate or chromium (VI) oxide.

Compounds of formulae II, VII, IX and XV may be prepared by reaction ofa compound of formula XVI,

wherein R^(y) represents —SO₂NH₂ (in the case of a compound of formulaII), —CONH₂ (in the case of a compound of formula VII), —NH₂ (in thecase of a compound of formula IX), or —CHO (in the case of a compound offormula XV) and R³, Z₁ and Z₂ are as hereinbefore defined, or aprotected derivative thereof, with a compound of formula XVII,

wherein L² represents a suitable leaving group, such as methylsulphonate(e.g. trifluoromethylsulphonate), or halo, such as iodo or bromo, andthe dotted line, X₁, X₂, X₃, A, Y₁, Y₂, Y₃ and Y₄ are as hereinbeforedefined, for example in the presence of an appropriate coupling catalystsystem (e.g. a palladium catalyst, such as Pd(PPh₃)₄ or Pd(OAc)₂/ligand(wherein the ligand may be, for example, PPh₃, P(o-Tol)₃ or1,1′-bis(diphenylphosphino)ferrocene)) and a suitable base (e.g. sodiumhydroxide, sodium carbonate, potassium carbonate, cesium carbonate,cesium fluoride, triethylamine or di-iso-propylethylamine), as well as asuitable solvent system (e.g. toluene, ethanol, dimethoxymethane,dimethylformamide, ethylene glycol dimethyl ether, water, dioxane ormixtures thereof). This reaction may be carried out at above roomtemperature (e.g. at a high temperature, such as the reflux temperatureof the solvent system that is employed). Preferably, compounds offormula XVI are protected at the R^(y) position prior to carrying outthe reaction with the compound of formula XVII. Suitable protectinggroups for different values of R^(y) are described hereinafter. If aprotected version of a compound of formula XVI is employed, thisreaction may be followed by deprotection of the R^(y) group understandard conditions, for example as described hereinafter.

Compounds of formulae II, VII, IX and XV may alternatively be preparedby reaction of a compound of formula XVIII,

wherein the dotted line, X₁, X₂ and X₃ are as hereinbefore defined witha compound of formula XIX,

wherein A, Y₁, Y₂, Y₃, Y₄, Z₁, Z₂, R^(y), R³ and L¹ are as hereinbeforedefined (L¹, in particular, may represent bromo), or a protected (at theR^(y) part) derivative thereof, for example at around, below or,preferably, above room temperature (e.g. at 80° C.), optionally in thepresence of a suitable base (e.g. potassium tert-butoxide, potassiumhydroxide, sodium hydroxide, sodium carbonate, triethylamine ordi-iso-propylethylamine) and an appropriate organic solvent (e.g. DMSO,dioxane, DMF, THF or CH₂Cl₂). In the case where base is not employed,the skilled person will appreciate that at least two equivalents of thecompound of formula XVIII may need to be employed. When A represents—CH₂—, suitable bases include potassium hydroxide and potassiumtert-butoxide and suitable solvents include DMSO, THF, DMF, dioxane orCH₂Cl₂. When A represents —C(O)—, suitable bases include triethylamineand di-iso-propylethylamine and suitable solvents include DMSO, DMF, THFand CH₂Cl₂. Suitable protecting groups for different values of R^(y) aredescribed hereinafter. If a protected version of a compound of formulaXIX is employed, this reaction may be followed by deprotection of theR^(y) group under standard conditions, for example as describedhereinafter.

Compounds of formula XVI and protected derivatives thereof may beprepared by reaction of a corresponding compound of formula XX,

wherein R^(y), R³, Z₁ and Z₂ are as hereinbefore defined, or anappropriate protected derivative thereof, with a reagent system thatwill enable the introduction of the —B(OH)₂ into the appropriate ringsystem. Suitable reagent systems include trialkylborates (e.g.tri-iso-propylborate). Such reactions may be carried out, for example,at low temperature (e.g. between −100° C. and 0° C., e.g. between −80°C. (such as −78° C.) and −10° C. (such as −20° C.)) in the presence of asuitable base (e.g. n-butyl lithium) and an appropriate organic solvent(e.g. THF), followed by acid hydrolysis (e.g. in the presence of diluteHCl).

Compounds of formula XVII may be prepared by standard techniques, forexample by way of reaction of a compound of formula XVIII ashereinbefore defined with a compound of formula XXI,

wherein A, Y₁, Y₂, Y₃, Y₄, L¹ and L² are as hereinbefore defined, forexample under similar conditions to those described hereinbefore inrespect of preparation of compounds of formulae II, VII, IX and XV(second process).

Compounds of formula XIX may be prepared by analogy with the processesdescribed in inter alia U.S. Pat. No. 5,312,820, UK patent applicationGB 2281298, and/or by reaction of a compound of formula XVI ashereinbefore defined with a compound of formula XXII,

wherein A, Y₁, Y₂, Y₃, Y₄ and L² are as hereinbefore defined, forexample under similar conditions to those described hereinbefore inrespect of preparation of compounds of formulae II, VII, IX and XV(first process), followed by conversion of the OH group in the resultantintermediate to an appropriate leaving group, L¹ (e.g., in the casewhere A is —CH₂— and L¹ is bromo, conversion may be carried out byreaction with CBr₄, for example at or around room temperature in thepresence of a base (e.g. triphenylphosphine) and a suitable organicsolvent (e.g. DMF). Alternatively, the hydroxyl group may be convertedto a sulfonate leaving group (e.g. mesylate or triflate) by employing asuitable reagent (e.g. a sulfonyl halide such as tosyl chloride, mesylchloride or triflic anhydride); similarly, when A represents —C(O)— andL¹ represents Cl, the intermediate acid may be reacted with SOCl₂ inbenzene or toluene, or with oxalyl chloride in DCM).

Compounds of formula XX are available using known techniques. Forexample:

-   (a) Compounds of formula XX in which R^(y) represents —S(O)₂NH₂,    —C(O)NH₂ or —CHO, and protected derivatives thereof, may be prepared    by reaction of a compound of formula XXIII,

-    wherein R^(ya) represents —S(O)₂NH₂, —C(O)NH₂ or —CHO and Z₁ and Z₂    are as hereinbefore defined, or a protected derivative thereof, with    a compound of formula XXIV,

R³L³  XXIV

-    wherein L³ represents a suitable leaving group (such as    toluenesulphonate, benzenesulphonate, methanesulphonate or halo,    such as bromo or iodo) and R³ is as hereinbefore defined, for    example at below room temperature (e.g. between around −35° C. and    around −85° C.), in the presence of a suitable base (e.g. n-butyl    lithium) and an appropriate solvent (e.g. THF).-   (b) Compounds of formula XX in which R^(y) is —S(O)₂NH₂ and    N-protected derivatives thereof, may be prepared by reaction of an    appropriate compound of formula XXV,

-    wherein R³, Z₁ and Z₂ are as hereinbefore defined with an    appropriate reagent for introduction of a —S(O)₂NH₂ group into the    appropriate ring system (for example chlorosulphonic acid, or    thionyl chloride in the presence of a suitable strong base (e.g.    butyl lithium)), followed by reaction of the resultant intermediate    with ammonia, or a protected derivative thereof (e.g.    tert-butylamine), under conditions that are well known to those    skilled in the art.-   (c) Certain protected derivatives (e.g. alkyl, such as C₁₋₆ alkyl,    for example tert-butyl, protected derivatives) of compounds of    formula XX in which R^(y) represents —C(O)NH₂ may be prepared by    reaction of a compound of formula XXV as hereinbefore defined, with    a compound of formula XXVI,

R^(Z)N═C═O  XXVI

-    wherein R^(Z) represents an appropriate protecting group, such as    an alkyl group, including C₁₋₆ alkyl, e.g. tert-butyl, for example    at low temperature (e.g. −78° C. to around 0° C.), in the presence    of a suitable base (e.g. n-butyl lithium) and an appropriate solvent    (e.g. THF).-   (d) Certain protected derivatives (e.g. alkyl, such as C₁₋₆ alkyl,    for example tert-butyl, protected derivatives) of compounds of    formula XX in which R^(y) represents —C(O)NH₂ may also be prepared    by reaction of a compound of formula XXVII,

-    wherein R³, Z₁ and Z₂ are as hereinbefore defined with a protected    (e.g. an (e.g. C₁₋₆) alkyl, such as tert-butyl-protected) derivative    of ammonia (e.g. tert-butylamine) under standard coupling conditions    (see, for example, those described hereinbefore for preparation of    compounds of formula I (process step (iii))). Compounds of formula    XXVII are known in the art or may be prepared by way of standard    techniques, for example oxidation of a corresponding compound of    formula XX in which R^(y) is —CHO e.g. under those conditions    described hereinbefore for preparation of compounds of formula V.-   (e) Compounds of formula XX in which R^(y) is —CHO, Z₁ represents    —CH═CH— and Z₂ represents —CH—, and protected derivatives thereof,    may be prepared by reaction of a compound of formula XXV in which Z₁    represents —CH═CH— and Z₂ represents —CH— with an appropriate    reagent system for the introduction of an aldehyde group into the    benzene ring (e.g. Zn(CN)₂ and HCl or, preferably, TiCl₄/CHCl₃,    SnCl₄/CH₂Cl₂ or 1,3,5,7-azaadamantane/TFA) under standard reaction    conditions, followed by (if appropriate) protection of the resultant    benzaldehyde under standard conditions.-   (f) Compounds of formula XX in which R^(y) is —NH₂, Z₁ represents    —CH═CH— and Z₂ represents —CH—, and N-protected derivatives thereof,    may be prepared by nitration of a compound of formula XXV in which    Z₁ represents —CH═CH— and Z₂ represents —CH—, followed by reduction    of the resultant nitrobenzene and (if appropriate) protection of the    resultant aminobenzene, all of which steps may be carried out under    standard conditions.

Compounds of formulae III, IV, VI, VIII, X, XI, XII, XIII, XIV, XVIII,XXI, XXII, XXIII, XXIV, XXV, XXVI and XXVII are either commerciallyavailable, are known in the literature, or may be obtained either byanalogy with the processes described herein, or by conventionalsynthetic procedures, in accordance with standard techniques, fromreadily available starting materials using appropriate reagents andreaction conditions.

Compounds of the invention may be isolated from their reaction mixturesusing conventional techniques.

It will be appreciated by those skilled in the art that, in theprocesses described above and hereinafter, the functional groups ofintermediate compounds may need to be protected by protecting groups.

Functional groups that it is desirable to protect include sulphonamido,amido, amino and aldehyde. Suitable protecting groups for sulphonamido,amido and amino include tert-butyloxycarbonyl, benzyloxycarbonyl,2-trimethylsilylethoxycarbonyl (Teoc) or tert-butyl. Suitable protectinggroups for aldehyde include alcohols, such as methanol or ethanol, anddiols, such as 1,3-propanediol or, preferably, 1,2-ethanediol (soforming a cyclic acetal).

The protection and deprotection of functional groups may take placebefore or after a reaction in the above-mentioned schemes.

Protecting groups may be removed in accordance with techniques that arewell known to those skilled in the art and as described hereinafter. Forexample, protected compounds/intermediates described herein may beconverted chemically to unprotected compounds using standarddeprotection techniques (e.g. using a protic acid or a Lewis acid suchas trifluoroacetic acid, sulfuric acid, toluenesulfonic acid, borontrichloride or Sc(OTf)₃).

Persons skilled in the art will appreciate that, in order to obtaincompounds of the invention in an alternative, and, on some occasions,more convenient, manner, the individual process steps mentionedhereinbefore may be performed in a different order, and/or theindividual reactions may be performed at a different stage in theoverall route (i.e. substituents may be added to and/or chemicaltransformations performed upon, different intermediates to thosementioned hereinbefore in conjunction with a particular reaction). Thismay negate, or render necessary, the need for protecting groups.

The type of chemistry involved will dictate the need, and type, ofprotecting groups as well as the sequence for accomplishing thesynthesis.

The use of protecting groups is fully described in “Protective Groups inOrganic Chemistry”, edited by J W F McOmie, Plenum Press (1973), and“Protective Groups in Organic Synthesis”, 3^(rd) edition, T. W. Greene &P. G. M. Wutz, Wiley-Interscience (1999).

Medical and Pharmaceutical Uses

Compounds of the invention are useful because they possesspharmacological activity. The compounds of the invention are thereforeindicated as pharmaceuticals.

According to a further aspect of the invention there is thus providedthe compounds of the invention for use as pharmaceuticals.

In particular, compounds of the invention are agonists of AngII, moreparticularly, are agonists of the AT2 receptor, and, especially, areselective agonists of that sub-receptor, for example as may bedemonstrated in the tests described below.

The compounds of the invention are thus expected to be useful in thoseconditions in which endogenous production of AngII is deficient and/orwhere an increase in the effect of AngII is desired or required.

The compounds of the invention are further expected to be useful inthose conditions where AT2 receptors are expressed and their stimulationis desired or required.

The compounds of the invention are further indicated in the treatment ofconditions characterised by vasoconstriction, increased cell growthand/or differentiation, increased cardiac contractility, increasedcardiovascular hypertrophy, and/or increased fluid and electrolyteretention.

The compounds of the invention are further indicated in the treatment ofstress-related disorders, and/or in the improvement of microcirculationand/or mucosa-protective mechanisms.

Thus, compounds of the invention are expected to be useful in thetreatment of disorders, which may be characterised as indicated above,and which are of, for example, the gastrointestinal tract, thecardiovascular system, the respiratory tract, the kidneys, the eyes, thefemale reproductive (ovulation) system and the central nervous system(CNS).

Disorders of the gastrointestinal tract that may be mentioned includeoesophagitis, Barrett's oesophagus, gastric ulcers, duodenal ulcers,dyspepsia (including non-ulcer dyspepsia), gastro-oesophageal reflux,irritable bowel syndrome (IBS), inflammatory bowel disease (IBD),pancreatitis, hepatic disorders (such as hepatitis), gall bladderdisease, multiple organ failure (MOF) and sepsis. Other gastrointestinaldisorders that may be mentioned include xerostomia, gastritis,gastroparesis, hyperacidity, disorders of the bilary tract, coelicia,Crohn's disease, ulcerative colitis, diarrhoea, constipation, colic,dysphagia, vomiting, nausea, indigestion and Sjögren's syndrome.

Disorders of the respiratory tract that may be mentioned includeinflammatory disorders, such as asthma, obstructive lung diseases (suchas chronic obstructive lung disease), pneumonitis, pulmonaryhypertension and adult respiratory distress syndrome.

Disorders of the kidneys that may be mentioned include renal failure,nephritis and renal hypertension.

Disorders of the eyes that may be mentioned include diabeticretinopathy, premature retinopathy and retinal microvascularisation.

Disorders of the female reproductive system that may be mentionedinclude ovulatory dysfunction.

Cardiovascular disorders that may be mentioned include hypertension,cardiac hypertrophy, cardiac failure, artherosclerosis, arterialthrombosis, venous thrombosis, endothelial dysfunction, endotheliallesions, post-balloon dilatation stenosis, angiogenesis, diabeticcomplications, microvascular dysfunction, angina, cardiac arrhythmias,claudicatio intermittens, preeclampsia, myocardial infarction,reinfarction, ischaemic lesions, erectile dysfunction and neointimaproliferation.

Disorders of the CNS that may be mentioned include cognitivedysfunctions, dysfunctions of food intake (hunger/satiety) and thirst,stroke, cerebral bleeding, cerebral embolus and cerebral infarction.

Compounds of the invention may also be useful in the modulation ofgrowth metabolism and proliferation, for example in the treatment ofhypertrophic disorders, prostate hyperplasia, autoimmune disorders,psoriasis, obesity, neuronal regeneration, the healing of ulcers,inhibition of adipose tissue hyperplasia, stem cell differentiation andproliferation, cancer (e.g. in the gastrointestinal tract, lung cancer,etc), apoptosis, tumours (generally) and hypertrophy, diabetes, neuronallesions and organ rejection.

The compounds of the invention are indicated both in the therapeuticand/or prophylactic treatment of the above conditions.

According to a further aspect of the present invention, there isprovided a method of treatment of a condition in which endogenousproduction of AngII is deficient, and/or a condition where an increasein the effect of AngII is desired or required, and/or a condition whereAT2 receptors are expressed and their stimulation is desired orrequired, which method comprises administration of a therapeuticallyeffective amount of a compound of the invention to a person sufferingfrom, or susceptible to, such a condition.

The compounds of the invention will normally be administered orally,intravenously, subcutaneously, buccally, rectally, dermally, nasally,tracheally, bronchially, by any other parenteral route or viainhalation, in a pharmaceutically acceptable dosage form.

When the condition to be treated is multiple organ failure, preferredroutes of administration are parenteral (e.g. by injection). Otherwise,the preferred route of administration for compounds of the invention isoral.

The compounds of the invention may be administered alone, but arepreferably administered by way of known pharmaceutical formulations,including tablets, capsules or elixirs for oral administration,suppositories for rectal administration, sterile solutions orsuspensions for parenteral or intramuscular administration, and thelike.

Such formulations may be prepared in accordance with standard and/oraccepted pharmaceutical practice.

According to a further aspect of the invention there is thus provided apharmaceutical formulation including a compound of the invention, inadmixture with a pharmaceutically acceptable adjuvant, diluent orcarrier.

Compounds of the invention may also be administered in combination withother AT2 agonists that are known in the art, as well as in combinationwith AT1 receptor antagonists that are known in the art, such aslosartan, or in combination with an inhibitor of angiotensin convertingenzyme (ACE).

According to a further aspect of the invention, there is provided acombination product comprising:

(A) a compound of the invention; and(B) an AT1 receptor antagonist, or an ACE inhibitor,wherein each of components (A) and (B) is formulated in admixture with apharmaceutically-acceptable adjuvant, diluent or carrier.

Such combination products provide for the administration of compound ofthe invention in conjunction with an AT1 receptor antagonist, or an ACEinhibitor, and may thus be presented either as separate formulations,wherein at least one of those formulations comprises compound of theinvention, and at least one comprises AT1 receptor antagonist, or ACEinhibitor, or may be presented (i.e. formulated) as a combinedpreparation (i.e. presented as a single formulation including compoundof the invention and AT1 receptor antagonist or ACE inhibitor).

Thus, there is further provided:

(1) a pharmaceutical formulation including a compound of the inventionand an AT1 receptor antagonist, or an ACE inhibitor, in admixture with apharmaceutically-acceptable adjuvant, diluent or carrier; and(2) a kit of parts comprising components:

-   (a) a pharmaceutical formulation including a compound of the    invention, in admixture with a pharmaceutically-acceptable adjuvant,    diluent or carrier; and-   (b) a pharmaceutical formulation including an AT1 receptor    antagonist, or an ACE inhibitor, in admixture with a    pharmaceutically-acceptable adjuvant, diluent or carrier,    which components (a) and (b) are each provided in a form that is    suitable for administration in conjunction with the other.

Depending upon the disorder and patient to be treated and the route ofadministration, the compounds of the invention may be administered atvarying doses.

Although doses will vary from patient to patient, suitable daily dosesare in the range of about 1 to 1000 mg per patient, administered insingle or multiple doses. More preferred daily doses are in the range2.5 to 250 mg per patient.

Individual doses of compounds of the invention may be in the range 1 to100 mg.

In any event, the physician, or the skilled person, will be able todetermine the actual dosage which will be most suitable for anindividual patient, which is likely to vary with the condition that isto be treated, as well as the age, weight, sex and response of theparticular patient to be treated. The above-mentioned dosages areexemplary of the average case; there can, of course, be individualinstances where higher or lower dosage ranges are merited, and such arewithin the scope of this invention.

Compounds of the invention have the advantage that they bind selectivelyto, and exhibit agonist activity at, the AT2 receptor. By compoundswhich “bind selectively” to the AT2 receptor, we include that theaffinity ratio for the relevant compound (AT2:AT1) is at least 5:1,preferably at least 10:1 and more preferably at least 20:1.

The compounds of the invention may also have the advantage that they maybe more efficacious than, be less toxic than, be longer acting than, bemore potent than, produce fewer side effects than, be more easilyabsorbed than, and/or have a better pharmacokinetic profile (e.g. higheroral bioavailability and/or lower clearance) than, and/or have otheruseful pharmacological, physical, or chemical properties over, compoundsknown in the prior art.

Biological Tests

The following test procedures may be employed.

Test A Receptor Binding Assay Using Rat Liver Membrane AT₁ Receptor

Rat liver membranes were prepared according to the method of Dudley etal (Mol. Pharmacol. (1990) 38, 370). Binding of [¹²⁵I]Ang II tomembranes was conducted in a final volume of 0.5 mL containing 50 mMTris-HCl (pH 7.4), 100 mM NaCl, 10 mM MgCl₂, 1 mM EDTA, 0.025%bacitracin, 0.2% BSA (bovine serum albumin), liver homogenatecorresponding to 5 mg of the original tissue weight, [¹²⁵I]Ang II (70000 cpm, 0.03 nM) and variable concentrations of test substance. Sampleswere incubated at 25° C. for 1 h, and binding was terminated byfiltration through Whatman GF/B glass-fiber filter sheets using aBrandel cell harvester. The filters were washed with 4×2 mL of Tris-HCl(pH 7.4) and transferred to tubes. The radioactivity was measured in agamma counter. The characteristics of the Ang II binding AT₁ receptorwere determined by using six different concentrations (0.03-5 nmol/L) ofthe labeled [¹²⁵I]AngII. Non-specific binding was determined in thepresence of 1 μM Ang II. The specific binding was determined bysubtracting the non-specific binding from the total bound [¹²⁵I]AngII.The dissociation constant (K_(d)=1.7±0.1 nM, [L]=0.057 nM) wasdetermined by Scatchard analysis of data obtained with Ang II by usingGraFit (Erithacus Software, UK). The binding data were best fitted witha one-site fit. All experiments were performed at least in triplicate.

Test B Receptor Binding Assay Using Porcine Myometrial Membrane AT₂Receptor

Myometrial membranes were prepared from porcine uteri according to themethod by Nielsen et al (Clin. Exp. Pharm. Phys. (1997) 24, 309). Anypossible interference that may be exhibited by binding of compound toAT₁ receptors was blocked by addition of 1 μM of a selective AT1inhibitor. Binding of [¹²⁵I]Ang II to membranes was conducted in a finalvolume of 0.5 mL containing 50 mM Tris-HCl (pH 7.4), 100 mM NaCl, 10 mMMgCl₂, 1 mM EDTA, 0.025% bacitracin, 0.2% BSA, homogenate correspondingto 10 mg of the original tissue weight, [¹²⁵I]Ang II (70 000 cpm, 0.03nM) and variable concentrations of test substance. Samples wereincubated at 25° C. for 1 h, and binding was terminated by filtrationthrough Whatman GF/B glass-fiber filter sheets using a Brandel cellharvester. The filters were washed with 3×3 mL of Tris-HCl (pH 7.4) andtransferred to tubes. The radioactivity was measured using a gammacounter. The characteristics of the Ang II binding AT₂ receptor wasdetermined by using six different concentrations (0.03-5 nmol/L) of thelabeled [¹²⁵I]Ang II. Non-specific binding was determined in thepresence of 1 μM Ang II. The specific binding was determined bysubtracting the non-specific binding from the total bound [¹²⁵I]Ang II.The dissociation constant (K_(d)=0.7±0.1 nM, [L]=0.057 nM) wasdetermined by Scatchard analysis of data obtained with Ang II by usingGraFit (Erithacus Software, UK). The binding data were best fitted witha one-site fit. All experiments were performed at least in triplicate.

Test C Duodenal Mucosal Alkaline Secretion Assay

Compounds were exposed to the duodenal mucosa inbarbiturate-anaesthetised rats prepared for in situ titration ofduodenal mucosal alkaline secretion, according to the methodologydescribed by Flemström et al in Am. J. Physiol. (1982) 243, G348.

The invention is illustrated by way of the following examples.

EXAMPLE 1N-Butyloxycarbonyl-3-(3-pyrrolidine-2,5-dione-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide(a) N-tert-Butylthiophene-2-sulfonamide

Thiophene-2-sulfonyl chloride (15 g, 0.082 mol) was dissolved in CHCl₃(200 mL) under N₂ atmosphere and then cooled to 0° C. tert-Butylamine(25.9 mL, 0.246 mol) dissolved in CHCl₃ (50 mL) was then added dropwiseto the reaction mixture. The reaction mixture was stirred for 1 h atroom temperature and then at reflux for 10 min. Toluene (700 mL) wasadded and the organic phase was washed with water (3×50 mL), dried, andconcentrated in vacuo. The sub-title product was used without furtherpurification in the next step.

¹H NMR δ (CDCl₃): 7.60 (1H, dd, J=1.3, 3.8 Hz), 7.53 (1H, dd, J=1.3, 5.0Hz), 7.02 (1H, dd, J=5.0, 3.8 Hz), 5.13 (1H, m), 1.24 (9H, m).

¹³C NMR δ (CDCl₃): 145.0, 131.7, 131.2, 127.0, 55.1, 29.9.

(b) 5-iso-Butyl-N-tert-butylthiophene-2-sulfonamide

N-tert-Butylthiophene-2-sulfonamide (10 g, 0.046 mol, see step (a)above) was dissolved in THF (85 mL) under N₂ and then cooled to −78° C.n-BuLi (1.6 M, 76.9 mL, 0.12 mol) was added via a syringe. The reactionmixture was stirred at −78° C. for 30 min. and then at −40° C. for 2 h.Iodo-2-methylpropane (10.5 mL, 0.09 mol) was added dropwise to thereaction mixture. The reaction mixture was stirred overnight at roomtemperature. The reaction was quenched with NH₄Cl (aq.) and extractedwith EtOAc. The combined organic phase was washed with brine and driedand concentrated in vacuo. The crude product was purified on columnchromatography (hexanes:EtOAc (10:1)) to give the sub-title compound in55% yield (7.0 g, 0.025 mol).

¹H NMR δ (CDCl₃): 7.43 (1H, d, J=3.6 Hz), 6.67 (1H, d, J=3.8 Hz), 4.83(1H, m), 2.67 (2H, d, J=7 Hz), 1.88 (1H, m), 1.26 (9H, m), 0.93 (6H,J=6.6 Hz).

¹³C NMR δ (CDCl₃): 145.0, 131.7, 131.2, 127.0, 55.1, 29.9.

(c) 5-iso-Butyl-2-(N-tert-butylaminosulfonyl)thiophene-3-boronic acid

5-iso-Butyl-N-tert-butylthiophene-2-sulfonamide (10.6 g, 0.039 mol, seestep (b) above) was dissolved in THF (165 mL) under N₂ and then cooledto −78° C. n-BuLi (1.6 M, 60.19 mL, 0.096 mol) was added via a syringe.The reaction mixture was stirred at −20° C. for 4 h. Thetri-iso-propylborate (13.3 mL, 0.058 mol) was then added via a syringeand the reaction mixture was stirred overnight at room temperature. Thereaction was quenched with 2 M HCl (20 mL). The organic phase wasseparated and the water phase was extracted with EtOAc (3×100 mL). Thecombined organic phase was washed with brine, dried and concentrated invacuo. The product was used without further purification. MS (ESI⁺) m/z:236.8

(d)3-(3-Hydroxymethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide

A mixture of m-bromobenzyl alcohol (1.05 g, 5.80 mmol),5-iso-butyl-2-(N-tert-butylaminosulfonyl)thiophene-3-boronic acid (2.41g, 7.55 mmol; see step (c)), Pd(PPh₃)₄ (270 mg, 0.235 mmol), NaOH (19.1mL, 1.5 M aq, 28.6 mmol), EtOH (5.0 mL) and toluene (30 mL) was stirredunder N₂ at 90° C. for about 4 h. After cooling, water (10 mL) was addedto the reaction mixture and this was then extracted with ethyl acetate.The combined organic phase was dried and concentrated in vacuo. Thecrude product was purified on column chromatography (EtOAc/hexane,30:70) to give sub-title compound as a colourless syrup in 57% yield(1.26 g, 3.31 mmol).

¹H NMR δ (CDCl₃): 0.96 (d, J=6.6 Hz, 6H), 0.98 (s, 9H), 1.82-2.00 (m,1H), 2.66 (d, J=7.1 Hz, 2H), 3.28 (br s, 1H), 4.67 (s, 2H), 4.81 (br s,1H), 6.76 (s, 1H), 7.30-7.50 (m, 3H), 7.64 (s, 1H).

¹³C NMR δ (CDCl₃): 22.1, 29.4, 30.4, 39.1, 54.4, 64.6, 127.1, 127.8,128.5, 129.0, 134.9, 136.2, 141.2, 143.2, 148.2.

MS (ESI) m/z: 382 (M+1)⁺.

IR ν (neat, cm⁻¹): 3498, 3286, 2958, 2870, 1465, 1313.

Anal. Calcd. for C₁₉H₂₇NO₃S₂: C, 59.81; H, 7.13; N, 3.67. Found: C,60.05; H, 7.31; N, 3.90.

(e)3-(3-Bromomethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide

A mixture of3-(3-hydroxymethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide(246 mg, 0.644 mmol; see step (d)), CBr₄ (534 mg, 1.61 mmol) and PPh₃(422 mg, 1.61 mmol) in DMF (5.0 mL) was stirred at room temperatureovernight. Water (10 mL) was then added and the reaction mixture wasextracted with ethyl acetate. The combined organic phase was washed withwater, dried and concentrated in vacuo. The crude product was purifiedon column chromatography (Hex/EtOAc 9:1) to give the sub-title compoundas a white solid in 95% yield (273 mg, 0.612 mmol).

¹H NMR δ (CDCl₃): 0.97 (d, J=6.3 Hz, 6H), 0.98 (s, 12H), 1.84-2.00 (m,1H), 2.69 (d, J=7.1 Hz, 2H), 4.18 (br s, 1H), 4.54 (s, 2H), 6.78 (s,1H), 7.37-7.44 (2H, m), 7.50-7.56 (m, 1H), 7.69 (br s, 1H).

¹³C NMR δ (CDCl₃): 22.2, 29.5, 30.5, 33.3, 39.2, 54.4, 128.6, 128.8,128.97, 129.02, 129.7, 135.5, 136.8, 138.3, 142.1, 148.5.

MS (ESI) m/z: 444 (M+H)⁺, 446 ((M+H)++2).

IR ν (neat, cm⁻¹): 3296, 2969, 2870, 1586, 1452, 1303.

Anal. Calcd. for C₁₉H₂₆BrNO₂S₂: C, 51.34; H, 5.90; N, 3.15. Found: C,51.44; H, 6.02; N, 3.22.

(f)3-(3-Pyrrolidine-2,5-dione-1-ylmethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide

To a solution of succinimide (66.6 mg, 0.672 mmol) in DMSO (1 mL) andt-BuOK (52.8 mg, 0.470 mmol), that had been stirred for 40 min atambient temperature, was added a solution of3-(3-bromomethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide(99.5 mg, 0.224 mmol; see step (e)) in DMSO (1 mL) dropwise. Thereaction mixture was stirred for 1 h at ambient temperature and thendiluted with CH₂Cl₂ (15 mL). The organic layer was washed with water,dried (over anhydrous MgSO₄), concentrated in vacuo, and the residuepurified by flash chromatography using MeOH:CH₂Cl₂ (3:97) as eluent togive the sub-title compound in 94% yield as a colourless syrup (97.1 mg,0.210 mmol).

¹H NMR δ (CDCl₃): 0.90 (s, 9H), 0.95 (d, J=6.6 Hz, 6H), 1.80-2.00 (m,1H), 2.65 (d, J=7.1 Hz, 2H), 2.83 (s, 4H), 4.59 (s, 1H), 4.75 (s, 2H),6.79 (s, 1H), 7.26-7.44 (m, 3H), 7.58 (m, 1H).

¹³C NMR δ (CDCl₃): 22.1, 28.4, 29.2, 30.4, 39.1, 41.7, 54.0, 126.6,127.1, 127.2, 128.2, 128.7, 135.0, 135.5, 136.7, 142.1, 148.3, 178.1.

IR ν (neat, cm⁻¹): 3306, 3058, 2960, 1708, 1702, 1428, 1400, 1321.

MS (ESI) m/z: 463 (M+H)⁺.

Anal. Calcd. for C₂₃H₃₀N₂O₄S₂: C, 59.71; H, 6.54; N, 6.06. Found: C,59.91; H, 6.74; N, 5.94.

(g)N-Butyloxycarbonyl-3-(3-pyrrolidine-2,5-dione-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide

To a solution of3-(3-pyrrolidine-2,5-dione-1-ylmethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide(95.0 mg, 0.205 mmol; see step (f)) in CH₂Cl₂ (2 mL) was added BCl₃ (0.6mL, 1.0 M in hexane) and the reaction mixture was stirred for 1 h atambient temperature. The reaction mixture was concentrated in vacuo.Water (5 mL) was added to the residue and this was then extracted withEtOAc. The combined organic phase was washed with water and brine, dried(over anhydrous MgSO₄) and concentrated in vacuo. To the crude productdissolved in pyridine (1.5 mL) was added pyrrolidinopyridine (91.3 mg,0.616 mmol) and butyl chloroformate (261.1 μL, 2.05 mmol) and thereaction mixture was stirred overnight. Citric acid (3 mL, 10% aq) wasadded to the reaction mixture, which was then extracted with EtOAc,dried (over anhydrous MgSO₄), concentrated in vacuo, and the residue waspurified by LCMS (Liquid Chromatography Mass Spectrum; 25-100% CH₃CN inwater) to give the title compound in 76% yield, over two steps, (79.1mg, 0.156 mmol).

¹H NMR δ (CDCl₃): 0.88 (t, J=7.3 Hz, 3H), 0.99 (d, J=6.6 Hz, 6H),1.16-1.34 (m, 2H), 1.46-1.58 (m, 2H), 1.86-2.04 (m, 1H), 2.71 (d, J=7.1Hz, 2H), 2.77 (s, 4H), 4.04 (t, J=6.7 Hz, 2H), 4.73 (s, 2H), 6.83 (s,1H), 7.24-7.42 (m, 3H), 7.67 (s, 1H), 8.74 (s, 1H).

¹³C NMR δ (CDCl₃): 13.6, 18.7, 22.2, 28.4, 30.4, 30.5, 39.3, 42.3, 66.6,127.8, 128.5, 128.6, 128.9, 129.0, 131.1, 134.1, 135.2, 144.9, 150.4,151.6, 178.2.

IR ν (neat, cm⁻¹): 3202, 2960, 2934, 2872, 1749, 1701, 1433, 1402, 1345,1159.

MS (ESI) m/z: 507 (M+H)⁺.

Anal. Calcd. for C₂₄H₃₀N₂O₆S₂: C, 56.90; H, 5.97; N, 5.53. Found: C,56.76; H, 5.89; N, 5.51.

EXAMPLE 2N-Butyloxycarbonyl-3-(3-pyrrolidine-2-one-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide(a)3-(3-Pyrrolidine-2-one-1-ylmethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide

To a solution of 2-pyrrolidinone (26.5 mg, 0.312 mmol) in DMSO (1 mL)and t-BuOK (48.9 mg, 0.436 mmol), that had been stirred for 40 min atambient temperature, was added a solution of3-(3-bromomethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide(92.3 mg, 0.208 mmol; see Example 1(e)) in DMSO (1 mL) dropwise. Thereaction mixture was stirred for 1 h at ambient temperature and thendiluted with CH₂Cl₂ (15 mL). The organic layer was washed with water,dried (over anhydrous MgSO₄), concentrated in vacuo, and the residuepurified by flash chromatography using MeOH:CH₂Cl₂ (2:98) as eluent togive the sub-title compound in 77% yield as a colourless syrup (72.3 mg,0.161 mmol).

¹H NMR δ (CDCl₃): 0.95 (d, J=6.6 Hz, 6H), 0.96 (s, 9H), 1.82-1.98 (m,1H), 2.00-2.14 (m, 2H), 2.51 (t, J=8.1 Hz, 2H), 2.66 (d, J=7.1 Hz, 2H),3.44 (t, J=7.1 Hz, 2H), 4.49 (s, 2H), 4.96 (s, 1H), 6.80 (s, 1H),7.19-7.27 (m, 1H), 7.34-7.42 (m, 2H), 7.60 (s, 1H).

¹³C NMR δ (CDCl₃): 17.9, 22.1, 29.4, 30.5, 30.8, 39.1, 46.5, 47.9, 54.1,127.1, 127.40, 127.45, 128.4, 128.6, 135.0, 136.7, 136.9, 142.1, 148.0,176.2.

IR ν (neat, cm⁻¹): 3206, 3058, 2960, 2871, 1671, 1465, 1434, 1313.

MS (ESI) m/z: 449 (M+H)⁺.

Anal. Calcd. for C₂₃H₃₂N₂O₃S₂: C, 61.57; H, 7.19; N, 6.24. Found: C,61.56; H, 7.31; N, 6.20.

(b)N-Butyloxycarbonyl-3-(3-pyrrolidine-2-one-1-ylmethylphenyl)-5-iso-butyl-thiophene-2-sulfonamide

To a solution of3-(3-pyrrolidine-2-one-1-ylmethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide(66.7 mg, 0.149 mmol; see step (a)) in CH₂Cl₂ (2 mL) was added BCl₃ (0.6mL, 1.0 M in hexane) and the reaction mixture was stirred for 1 h atambient temperature. The reaction mixture was concentrated in vacuo.Water (5 mL) was added to the residue and this was then extracted withEtOAc. The combined organic phase was washed with water and brine, dried(over anhydrous MgSO₄) and concentrated in vacuo. To the crude productdissolved in pyridine (1.5 mL) was added pyrrolidinopyridine (44.1 mg,0.297 mmol) and butyl chloroformate (189.1 μL, 1.49 mmol) and thereaction mixture was stirred overnight. Citric acid (3 mL, 10% aq) wasadded to the reaction mixture, which was then extracted with EtOAc,dried (over anhydrous MgSO₄), concentrated in vacuo, and the residuepurified by LCMS (20-100% CH₃CN in water) to give the title compound in74% yield, over two steps, (54 mg, 0.110 mmol).

¹H NMR δ (CDCl₃): 0.88 (t, J=7.2 Hz, 3H), 0.98 (d, J=6.6 Hz, 6H),1.20-1.40 (m, 2H), 1.50-1-65 (m, 2H), 1.85-2.10 (m, 3H), 2.47 (t, J=8.0Hz, 2H), 2.70 (d, J=7.1 Hz, 2H), 3.44 (t, J=7.1 Hz, 2H), 4.08 (t, J=6.8Hz, 2H), 4.44 (s, 2H), 6.86 (s, 1H), 7.15-7.23 (m, 1H), 7.29-7.40 (m,2H), 7.80 (s, 1H), 10.04 (br s, 1H).

¹³C NMR δ (CDCl₃): 13.6, 17.8, 18.8, 22.2, 30.4, 30.5, 31.2, 39.3, 47.2,47.9, 66.4, 127.6, 127.8, 128.2, 128.3, 129.7, 131.4, 134.3, 136.3,144.6, 151.0, 151.3, 177.2.

IR ν (neat, cm⁻¹): 3051, 2959, 2871, 1747, 1662, 1466, 1347.

MS (ESI) m/z: 493 (M+H)⁺.

Anal. Calcd. for C₂₄H₃₂N₂O₅S₂: C, 58.51; H, 6.55; N, 5.69. Found: C,58.35; H, 6.63; N, 5.75.

EXAMPLE 3N-Butyloxycarbonyl-3-[3-(3-methylimidazolidine-2,5-dione-1-ylmethyl)phenyl]-5-iso-butylthiophene-2-sulfonamide(a)3-[3-(3-Methylimidazolidine-2,5-dione-1-ylmethyl)phenyl]-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide

To a solution of 1-methylhydantoin (33.9 mg, 0.297 mmol) in DMSO (1 mL)and t-BuOK (46.6 mg, 0.415 mmol), that had been stirred for 40 min atambient temperature, was added a solution of3-(3-bromomethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide(87.9 mg, 0.198 mmol; see Example 1(e)) in DMSO (1 mL) dropwise. Thereaction mixture was stirred for 1 h at ambient temperature and thendiluted with CH₂Cl₂ (15 mL). The organic layer was washed with water,dried (over anhydrous MgSO₄), concentrated in vacuo, and the residuepurified by flash chromatography using EtOAc:petroleum ether (35:65) aseluent to give the sub-title compound in 54% yield as a colourless syrup(51.5 mg, 0.107 mmol).

¹H NMR δ (CDCl₃): 0.90 (s, 9H), 0.95 (d, J=6.6 Hz, 6H), 1.82-1.98 (m,1H), 2.66 (d, J=6.8 Hz, 2H), 3.03 (s, 3H), 4.02 (s, 2H), 4.77 (s, 2H),4.99 (s, 1H), 6.81 (s, 1H), 7.26-7.44 (m, 3H), 7.69 (m, 1H).

¹³C NMR δ (CDCl₃): 22.1, 29.3, 29.8, 30.5, 39.2, 41.9, 52.0, 53.9,126.7, 126.9, 127.2, 128.2, 128.7, 135.0, 135.9, 136.9, 142.1, 148.2,157.0, 170.5.

MS (ESI) m/z: 478 (M+H)⁺.

IR ν (neat, cm⁻¹): 3276, 3057, 2960, 2870, 1771, 1716, 1488, 1451, 1317.

Anal. Calcd. for C₂₃H₃₁N₃O₄S₂: C, 57.84; H, 6.54; N, 8.80. Found: C,58.02; H, 6.77; N, 8.93.

(b)N-Butyloxycarbonyl-3-[3-(3-methylimidazolidine-2,5-dione-1-ylmethyl)-phenyl]-5-iso-butylthiophene-2-sulfonamide

To a solution of3-[3-(3-methylimidazolidine-2,5-dione-1-ylmethyl)phenyl]-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide(42.1 mg, 0.088 mmol; see step (a)) in CH₂Cl₂ (2 mL) was added BCl₃ (0.6mL, 1.0 M in hexane) and the reaction mixture was stirred for 1 h atambient temperature. The reaction mixture was concentrated in vacuo.Water (5 mL) was added to the residue and this was then extracted withEtOAc. The combined organic phase was washed with water, and brine,dried (over anhydrous MgSO₄) and concentrated in vacuo. To the crudeproduct dissolved in pyridine (1.5 mL) was added pyrrolidinopyridine(26.1 mg, 0.176 mmol) and butyl chloroformate (112.0 μL, 0.88 mmol) andthe reaction mixture was stirred overnight. Citric acid (3 mL, 10% aq)was added to the reaction mixture, which was then extracted with EtOAc,dried (over anhydrous MgSO₄), concentrated in vacuo, and the residuepurified by flash chromatography using MeOH:CH₂Cl₂ (3:97) as eluent andthen with LCMS (30-100% CH₃CN in water) to give the title compound in80% yield, over two steps, (36.6 mg, 0.702 mmol).

¹H NMR δ (CDCl₃): 0.86 (t, J=7.2 Hz, 3H), 0.98 (d, J=6.7 Hz, 6H),1.15-1.30 (m, 2H), 1.42-1.58 (m, 2H), 1.88-2.04 (m, 1H), 2.70 (d, J=6.9Hz, 2H), 3.00 (s, 3H), 3.94 (s, 2H), 4.00 (t, J=6.6 Hz, 2H), 4.73 (s,2H), 6.85 (s, 1H), 7.22-7.32 (m, 1H), 7.32-7.44 (m, 2H), 7.75 (s, 1H),9.26 (br s, 1H).

¹³C NMR δ (CDCl₃): 13.6, 18.7, 22.2, 29.7, 30.41, 30.45, 39.3, 42.4,51.9, 66.4, 127.7, 128.4, 128.85, 128.93, 131.3, 134.0, 135.6, 144.6,150.5, 151.3, 157.1, 170.2.

IR ν (neat, cm⁻¹): 3124, 2959, 2933, 2872, 1750, 1702, 1488, 1452, 1345.

MS (ESI) m/z: 522 (M+H)⁺.

Anal. Calcd. for C₂₄H₃₁N₃O₆S₂×1½H₂O: C, 52.54; H, 6.25; N, 7.66. Found:C, 52.25; H, 6.05; N, 7.91.

EXAMPLE 4

Title compounds of the Examples were tested in Tests A and B above andwere found to exhibit an affinity for AT2 receptors of less than Ki=100nM (e.g. less than 50 nM). The title compounds of the Examples werefound to exhibit an affinity to AT1 receptors of more than Ki=500 nM(e.g. more than 1 μM).

EXAMPLE 5

Title compounds of the Examples are tested in Test C above and are foundto stimulate markedly mucosal alkalisation. This effect is blocked byco-administration of the selective AT2 receptor antagonist PD123319(Sigma Chemical Company).

1. A compound of formula I,

wherein X¹ represents —C(R^(1a))(R^(1b))—, —N(R^(1a))— or —O—; thedotted line signifies an optional double bond; and in the case when thedotted line does not signify a double bond, X₂ and X₃ independentlyrepresent —C(R^(1c))(R^(1d))—, —N(R^(1e))—, —O—, —C(O)— or—C(R^(1f))(R^(1g))—C(R^(1h))(R^(1j))— provided that: (i) when X₁represents —N(R^(1a))—, then X₂ and X₃ do not both represent—N(R^(1e))—; (ii) when X₁ represents —O—, then X₂ and X₃ do not bothrepresent —O—; (iii) when X₁ represents —O— and X₂ represents—N(R^(1e))—, then X₃ represents —C(O)—; and (iv) when X₁ represents —O—and X₃ represents —N(R^(1e))—, then X₂ does not represent—C(R^(1c))(R^(1d))—; or in the case when the dotted lines signifies adouble bond, X² and X³ independently represent —N— or —C(R^(1c))—;R^(1a), R^(1b), R^(1c), R^(1d), R^(1e), R^(1f), R^(1g), R^(1h) andR^(1j) independently represent H, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆alkoxy-C₁₋₆ alkyl, Ar¹, Het¹, C₁₋₃ alkyl-Ar², C₁₋₃ alkyl-Het², C₁₋₃alkoxy-Ar³, C₁₋₃ alkoxy-Het³, halo, —C(O)—C₁₋₆ alkyl, —C(O)—Ar⁴ or—C(O)—Het⁴; Ar¹, Ar², Ar³ and Ar⁴ each independently represent a C₆₋₁₀aryl group, which group is optionally substituted by one or moresubstituents selected from ═O, —OH, cyano, halo, nitro, C₁₋₆ alkyl(optionally terminated by —N(H)C(O)OR^(11a)), C₁₋₆ alkoxy, phenyl,—N(R^(12a))R^(12b), —C(O)R^(12c), —C(O)OR^(12d), —C(O)N(R^(12e))R^(12f),—N(R^(12g))C(O)R^(12h), —N(R^(12i))C(O)N(R^(12j))R^(12k),—N(R^(12m))S(O)₂R^(11b), —S(O)_(p)R^(11c), —OS(O)₂R^(11d) and—S(O)₂N(R^(12n))R^(12p); Het¹, Het², Het³ and Het⁴ each independentlyrepresent a four- to twelve-membered heterocyclic group containing oneor more heteroatoms selected from oxygen, nitrogen and/or sulfur, whichheterocyclic group is optionally substituted by one or more substituentsselected from ═O, —OH, cyano, halo, nitro, C₁₋₆ alkyl (optionallyterminated by —N(H)C(O)OR^(11a)), C₁₋₆ alkoxy, phenyl,—N(R^(12a))R^(12b), —C(O)R^(12c), —C(O)OR^(12d), —C(O)N(R^(12e))R^(12f),—N(R^(12g))C(O)R^(12h), —N(R^(12i))C(O)N(R^(12j))R^(12k),—N(R^(12m))S(O)₂R^(11b), —S(O)_(p)R^(11c), —OS(O)₂R^(11d) and—S(O)₂N(R^(12n))R^(12p); R^(11a) to R^(11d) independently represent C₁₋₆alkyl; R^(12a) to R^(12p) independently represent H or C₁₋₆ alkyl; prepresents 0, 1 or 2; A represents —C(O) or —CH₂—; Y₁, Y₂, Y₃ and Y₄independently represent —CH— or —CF—; Z₁ represents —CH—, —O—, —S—, —N—or —CH═CH—; Z₂ represents —CH—, —O—, —S— or —N—; provided that: (a) Z₁and Z₂ are not the same; (b) when Z₁ represents —CH═CH—, then Z₂ mayonly represent —CH— or —N—; and (c) other than in the specific case inwhich Z₁ represents —CH═CH—, and Z₂ represents —CH—, when one Z₁ and Z₂represents —CH—, then the other represents —O— or —S—; R² represents—S(O)₂N(H)C(O)R⁴, —S(O)₂N(H)S(O)₂R⁴, —C(O)N(H)S(O)₂R⁴, or, when Z₁represents —CH═CH—, R² may represent —N(H)S(O)₂N(H)C(O)R⁵ or—N(H)C(O)N(H)S(O)₂R⁵; R³ represents C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆alkoxy-C₁₋₆-alkyl or di-C₁₋₃-alkylamino-C₁₋₄-alkyl; R⁴ represents C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxy-C₁₋₆-alkyl, C₁₋₃ alkoxy-C₁₋₆-alkoxy,C₁₋₆ alkylamino or di-C₁₋₆ alkylamino; and R⁵ represents C₁₋₆ alkyl, ora pharmaceutically-acceptable salt thereof.
 2. A compound as claimed inclaim 1, wherein the dotted line does not signify a double bond.
 3. Acompound as claimed in claim 1, wherein X₁ represents—C(R^(1a))(R^(1b))— or —N(R^(1a))—.
 4. A compound as claimed in claim 3,wherein X₁ represents —CH₂— or —N(CH₃)—.
 5. A compound as claimed inclaim 1, wherein X₂ represents —O—, —N(R^(1e))— or —C(R^(1c))(R^(1d))—.6. A compound as claimed in claim 5, wherein X₂ represents —CH₂—.
 7. Acompound as claimed in claim 1, wherein X₃ represents —O—,—C(R^(1f))(R^(1g))—C(R^(1h))(R^(1j))—, —C(R^(1c))(R^(1d))— or —C(O)—. 8.A compound as claimed in claim 7, wherein X₃ represents —CH₂— or —C(O)—.9. A compound as claimed in claim 1, wherein A represents —CH₂—.
 10. Acompound as claimed in claim 1, wherein Y₁, Y₂, Y₃ and Y₄ all represent—CH—.
 11. A compound as claimed in claim 1, wherein Z₁ represents —S— or—CH═CH—.
 12. A compound as claimed in claim 11, wherein Z₁ represents—S—.
 13. A compound as claimed in claim 1, wherein Z₂ represents —CH—.14. A compound as claimed in claim 1, wherein R³ represents C₁₋₄ alkyl.15. A compound as claimed in claim 14, wherein R³ represents iso butyl.16. A compound as claimed in claim 1, wherein, when R² represents—S(O)₂N(H)C(O)R⁴, —S(O)₂N(H)S(O)₂R⁴ or —C(O)N(H)S(O)₂R⁴, R⁴ representsn-butoxymethyl, isobutoxy or n-butoxy.
 17. A compound as claimed inclaim 1, wherein R² represents —S(O)₂N(H)C(O)R⁴.
 18. A compound asclaimed in claim 17, wherein R⁴ represents n-butoxymethyl, isobutoxy orn-butoxy.
 19. A compound as claimed in claim 16, wherein R⁴ representsn-butoxy.
 20. A pharmaceutical formulation including a compound asdefined in claim 1, or a pharmaceutically acceptable salt thereof, inadmixture with a pharmaceutically acceptable adjuvant, diluent orcarrier.
 21. A compound as defined in claim 1, or a pharmaceuticallyacceptable salt thereof, for use as a pharmaceutical.
 22. A compound asdefined in claim 1, or a pharmaceutically acceptable salt thereof, foruse in the treatment of a condition in which selective agonism of theAT2 receptor is desired and/or required.
 23. A compound as defined inclaim 1, or a pharmaceutically acceptable salt thereof, for use in thetreatment of a condition in which endogenous production of AngII isdeficient.
 24. A compound as defined in claim 1, or a pharmaceuticallyacceptable salt thereof, for use in the treatment of a condition inwhich an increase in the effect of AngII is desired or required.
 25. Acompound as defined in claim 1, or a pharmaceutically acceptable saltthereof, for use in the treatment of a condition where AT2 receptors areexpressed and their stimulation is desired or required.
 26. The use of acompound as defined in claim 1, or a pharmaceutically acceptable saltthereof, for the manufacture of a medicament for the treatment of acondition in which selective agonism of the AT2 receptor is desiredand/or required.
 27. The use of a compound as defined in claim 1, or apharmaceutically acceptable salt thereof, for the manufacture of amedicament for the treatment of a condition in which endogenousproduction of AngII is deficient.
 28. The use of a compound as definedin claim 1, or a pharmaceutically acceptable salt thereof, for themanufacture of a medicament for the treatment of a condition in which anincrease in the effect of AngII is desired or required.
 29. The use of acompound as defined in claim 1, or a pharmaceutically acceptable saltthereof, for the manufacture of a medicament for the treatment of acondition where AT2 receptors are expressed and their stimulation isdesired or required.
 30. The use as claimed in claim 26, wherein thecondition is of the gastrointestinal tract, the cardiovascular system,the respiratory tract, the kidneys, the eyes, the female reproductive(ovulation) system, or the central nervous system.
 31. The use asclaimed in claim 30, wherein the condition is oesophagitis, Barrett'soesophagus, a gastric ulcer, a duodenal ulcer, dyspepsia (includingnon-ulcer dyspepsia), gastro-oesophageal reflux, irritable bowelsyndrome, inflammatory bowel disease, pancreatitis, hepatic disorders(including hepatitis), gall bladder disease, multiple organ failure,sepsis, xerostomia, gastritis, gastroparesis, hyperacidity, a disorderof the bilary tract, coelicia, Crohn's disease, ulcerative colitis,diarrhoea, constipation, colic, dysphagia, vomiting, nausea,indigestion, Sjögren's syndrome, inflammatory disorders, asthma, anobstructive lung disease (including chronic obstructive lung disease),pneumonitis, pulmonary hypertension, adult respiratory distresssyndrome, renal failure, nephritis, renal hypertension, diabeticretinopathy, premature retinopathy, retinal microvascularisation,ovulatory dysfunction, hypertension, cardiac hypertrophy, cardiacfailure, artherosclerosis, arterial thrombosis, venous thrombosis,endothelial dysfunction, endothelial lesions, post balloon dilatationstenosis, angiogenesis, diabetic complications, microvasculardysfunction, angina, cardiac arrhythmias, claudicatio intermittens,preeclampsia, myocardial infarction, reinfarction, ischaemic lesions,erectile dysfunction, neointima proliferation, cognitive dysfunctions,dysfunctions of food intake (hunger/satiety), thirst, stroke, cerebralbleeding, cerebral embolus, cerebral infarction, hypertrophic disorders,prostate hyperplasia, autoimmune disorders, psoriasis, obesity, neuronalregeneration, an ulcer, adipose tissue hyperplasia, stem celldifferentiation and proliferation, cancer, apoptosis, tumours,hypertrophy diabetes, neuronal lesions or organ rejection.
 32. The useas claimed in claim 31, wherein the condition is non-ulcer dyspepsia,irritable bowel syndrome, multiple organ failure, hypertension orcardiac failure.
 33. A method of treatment of a condition in whichselective agonism of the AT2 receptor is desired and/or required, whichmethod comprises administration of a therapeutically effective amount ofa compound as defined in claim 1, or a pharmaceutically acceptable saltthereof, to a person suffering from, or susceptible to, such acondition.
 34. A pharmaceutical formulation including a compound asdefined in claim 1, or a pharmaceutically acceptable salt thereof, andan AT1 receptor antagonist, in admixture with apharmaceutically-acceptable adjuvant, diluent or carrier.
 35. A kit ofparts comprising components: (a) a pharmaceutical formulation includinga compound as defined in claim 1, or a pharmaceutically acceptable saltthereof, in admixture with a pharmaceutically-acceptable adjuvant,diluent or carrier; and (b) a pharmaceutical formulation including anAT1 receptor antagonist, in admixture with a pharmaceutically-acceptableadjuvant, diluent or carrier, which components (a) and (b) are eachprovided in a form that is suitable for administration in conjunctionwith the other.
 36. A pharmaceutical formulation including a compound asdefined in claim 1, or a pharmaceutically acceptable salt thereof, andan angiotensin converting enzyme inhibitor, in admixture with apharmaceutically-acceptable adjuvant, diluent or carrier.
 37. A kit ofparts comprising components: (a) a pharmaceutical formulation includinga compound as defined in claim 1, or a pharmaceutically acceptable saltthereof, in admixture with a pharmaceutically-acceptable adjuvant,diluent or carrier; and (b) a pharmaceutical formulation including anangiotensin converting enzyme inhibitor, in admixture with apharmaceutically-acceptable adjuvant, diluent or carrier, whichcomponents (a) and (b) are each provided in a form that is suitable foradministration in conjunction with the other.
 38. A process for thepreparation of a compound as defined in claim 1, which comprises: (i)for compounds of formula I in which R² represents —S(O)₂N(H)C(O)R⁴ or—S(O)₂N(H)S(O)₂R⁴, and R⁴ is as defined in claim 1, reaction of acompound of formula II,

wherein the dotted line, X₁, X₂, X₃, A, Y₁, Y₂, Y₃, Y₄, Z₁, Z₂ and R³are as defined in claim 1 with a compound of formula III,R⁴GL¹  III wherein G represents —C(O)— or —S(O)₂— (as appropriate), L¹represents a suitable leaving group and R⁴ is as defined in claim 1;(ii) for compounds of formula I in which R² represents —S(O)₂N(H)C(O)R⁴and R⁴ represents C₁₋₆ alkoxy-C₁₋₆-alkyl, coupling of a compound offormula II as defined above with a compound of formula IV,R^(4a)CO₂H  IV wherein R^(4a) represents C₁₋₆ alkoxy-C₁₋₆-alkyl; (iii)for compounds of formula I in which R² represents —C(O)N(H)S(O)₂R⁴ andR⁴ is as defined in claim 1, coupling of a compound of formula V,

wherein the dotted line, X₁, X₂, X₃, A, Y₁, Y₂, Y₃, Y₄, Z₁, Z₂ and R³are as defined in claim 1 with a compound of formula VI,R⁴S(O)₂NH₂  VI wherein R⁴ is as defined in claim 1; (iv) for compoundsof formula I in which R² represents —C(O)N(H)S(O)₂R⁴ and R⁴ is asdefined in claim 1, coupling of a compound of formula VII,

wherein the dotted line, X₁, X₂, X₃, A, Y₁, Y₂, Y₃, Y₄, Z₁, Z₂ and R³are as defined in claim 1 with a compound of formula VIII,R⁴S(O)₂Cl  VIII wherein R⁴ is as defined in claim 1; (v) for compoundsof formula I in which R² represents —N(H)S(O)₂N(H)C(O)R⁵ and R⁵ is asdefined in claim 1, reaction of a compound of formula IX,

wherein the dotted line, X₁, X₂, X₃, A, Y₁, Y₂, Y₃, Y₄, Z₁, Z₂ and R³are as defined in claim 1 with a compound of formula X,R⁵C(O)N(H)S(O)₂Cl  X wherein R⁵ is as defined in claim 1; (vi) forcompounds of formula I in which R² represents —N(H)C(O)N(H)S(O)₂R⁵ andR⁵ is as defined in claim 1, reaction of a compound of formula IX asdefined above with a compound of formula XI,R⁵S(O)₂N(H)C(O)R^(x)  XI wherein R^(x) represents a suitable leavinggroup and R⁵ is as defined in claim 1; (vii) for compounds of formula Iin which R² represents —N(H)C(O)N(H)S(O)₂R⁵ and R⁵ is as defined inclaim 1, reaction of a compound of formula IX as defined above with acompound of formula XII,R⁵S(O)₂NCO  XII wherein R⁵ is as defined in claim 1; (viii) forcompounds of formula I in which R² represents —S(O)₂N(H)C(O)R⁴ and R⁴represents C₁₋₆ alkylamino, reaction of a compound of formula II asdefined above with a compound of formula XIII,R^(4b)NCO  XIII wherein R^(4b) is C₁₋₆ alkyl; or (ix) for compounds offormula I in which R² represents —S(O)₂N(H)C(O)R⁴ and R⁴ representsdi-C₁₋₆ alkylamino, reaction of a corresponding compound of formula I inwhich R² represents —S(O)₂N(H)C(O)R⁴ and R⁴ represents C₁₋₆ alkoxy witha compound of formula XIV,R^(4c)N(H)R^(4d)  XIV wherein R^(4c) and R^(4d) independently representC₁₋₆ alkyl.
 39. A compound of formula II as defined in claim 38 or aprotected derivative thereof.
 40. A compound of formula V as defined inclaim 38 or a protected derivative thereof.
 41. A compound of formulaVII as defined in claim 38 or a protected derivative thereof.
 42. Acompound of formula IX as defined in claim 38 or a protected derivativethereof.